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Studies elucidating the role of p38α MAPK in diverse biological processes are limited by the lack of a specific inhibitor. Skepinone-L is a highly selective ATP-competitive inhibitor of p38 with excellent potency in vivo.
Compounds containing a primary amino group can protect against light-induced retinal degeneration in a mouse model of Stargardt’s disease and age-related retinal degeneration by forming a transient Schiff base with all-trans-retinal, lowering its intracellular concentration and preventing accumulation of lipofuscin chromophores in the eye.
Screens of large compound libraries identify new small–molecule proteostasis regulators that, by enhancing the activity of the heat shock response factor HSF–1 and by activating other components of the proteostasis network, such as the antioxidant response or the unfolded protein response pathways, restore protein folding in multiple models of protein conformational diseases.
Natural product–inspired compounds are primed to interact with and manipulate biological processes, but obtaining these complex molecules poses synthetic challenges. The development of a 12-step, 1-pot cascade reaction leads to the 'centrocountins', tetrahydroindoloquinolizines that modulate mitosis by targeting the centrosome-associated proteins nucleophosmin and Crm1.
The four subunits of the tetrameric voltage-sensitive HCN channel have different cAMP binding affinities, with the second and fourth binding events being positively cooperative and the third being negatively cooperative, suggesting a double-dimeric organization of the channel.
A cheminformatics approach helps identify proteins such as GPCRs, ion channels and kinases that are targeted by small molecules that give phenotypes in a zebrafish behavioral assay.
Threading of a polypeptide chain is required for knotted proteins to adopt active conformations. A cell-free translation system in conjunction with pulse proteolysis to track folding of trefoil knotted proteins reveal that these knots form spontaneously, but GroEL–GroES enhances the rate of post-translational knot formation.
Polyketide synthases make use of a limited set of enzymes to create diverse natural products. The discovery that a ketosynthase homolog catalyzes ester bond formation instead of the typical Claisen condensation uncovers a previously unknown mechanism to generate chemical diversity.
Lysophosphatidic acid, a lipid mediator, second messenger and intermediate in lipid biosynthesis, finds a new intracellular target in TRPV1. This nonselective cation channel is also targeted by the analgesic capsaicin, which acts to desensitize the channel.
Understanding the molecules and mechanisms that microbes use to interact with each other and their environments can lead to better antimicrobial drug design as well as a richer understanding of bacterial physiology, ecology and evolution.
The multisubunit DNA polymerases of eukaryotes have iron-sulfur centers that are crucial for polymerase assembly and therefore the integrity of the nuclear genome.
Amino acids not only are useful for protein synthesis but also act as regulators of gene expression. An elegant genome-wide approach now shows how binding of amino acids to transcription factors regulates an integrated network of amino acid metabolism to suit the physiological needs of bacterial cells.
